Neuromyelitis optica (NMO) is a severe, relapsing IgG-mediated autoimmune disease targeting the central nervous system (CNS), inducing inflammation and preferential demyelination of optic nerve and spinal cord. Most patients experience severe impairments. IgG autoantibodies specific for the astrocytic aquaporin-4 (AQP4) water channel are the primary cause of the disease pathophysiology. However, little is known about the mechanisms driving NMO lesion progression following the binding of IgG to the astrocyte membrane on entering the CNS. Our proposed project will investigate the potential contribution of microglia, the resident immune cell of the CNS, to the evolving NMO lesion. We have developed an informative mouse model of NMO. NMO-IgG is infused intrathecally. Our preliminary results show significant motor dysfunction, astrocyte activation, and a unique pattern of early microglial convergence on astrocytes. Prevention of microglial activity suppressed development of motor dysfunction. In sum, these data clearly indicate astrocyte-microglia communication as an early event after NMO-IgG enters the CNS. Aim 1, will investigate the mechanisms underlying astrocyte-microglia crosstalk; Aim 2, will assess the contribution of microglia to NMO pathogenesis, and Aim 3 will utilize novel genetic tools to manipulate microglial activity as a potential therapeutic approach to NMO management. The research we propose represents the first attempt to investigate the specific contribution of microglia to NMO pathogenesis. The results should clarify the importance of astrocyte-microglia crosstalk and its underlying mechanisms in NMO. The study will not only improve understanding of neuroimmune interaction in NMO but will potentially establish that microglia are a pertinent target for NMO therapy.